The focus of this renewal application is on the traffic and accumulation of monocyte/macrophages in the central nervous system (CNS) in neuro-AIDS. In the previous funding period, we established immune-phenotypic differences between perivascular macrophages and parenchymal microglia, and identified perivascular macrophages as a primary target of productive SIV infection at viremia and terminally with AIDS. Our focus in upcoming period is to identify potential precursors to CNS perivascular macrophages within the bone marrow and blood and to study their activation, expansion, and infection by SIV. We hypothesize that monocytelmacrophages, which can carry virus to the CNS, can be identified in the bone marrow and blood; the immune system controls the infection, activation, and expansion of these cells; and that traffic and accumulation of these infected monocytes that become perivascular macrophages contribute to productive CNS infection. We propose 3 specific aims to study these hypotheses. Studies in Aim 1 propose to identify monocyte/macrophages in the bone marrow and blood that have a similar immune phenotype of CNS perivascular macrophages, to define subpopulations that are SIV-infected at viremia and with AIDS, to determine the timing of latent and productive infection, and to identify populations that have similar env sequences. Studies in aim 2 propose to determine the role of the peripheral immune system and CD4 + and CD8 +specific T lymphocyte responses and CTL function in controlling infection, activation, and expansion of bone marrow and blood monocyte/macrophages with immune phenotypes similar to CNS perivascular macrophages. Studies in aim 3 propose to define the timing of SIV-infected monocyte entry that contributes to productive infection of the CNS.